In recent years, there has been considerable progress in defining the viral and host genetic factors affecting Hepatitis C viral pathogenesis. However, many gaps still remain. With epidemic levels of injection drug use, Southeast Asia carries the largest burden of HCV infections and emerging HlV-1 infections. In China alone, the WHO estimates 2.5-4.9% of the overall population is HCV seropositive. With a population of over 1.2 billion persons, HCV may affect close to 50 million individuals in China. Previous cohort studies have included mainly Caucasian and African American ethnicities and dominated by HCV genotype 1 infections. The purpose of this study is to determine the effect of viral and host genetic factors and HIV-1 co-infection on HCV clearance, immunity and disease progression in an established cohort of injection drug users from Southern China. Within this cohort extremely high rates of HCV transmission and high genotype diversity have been documented. The distribution and transmission patterns of HCV genotypes in these IDUS are also being studied, in this application, we propose to carry out the following specific aims (1) To study the influence of viral characteristics on HCV clearance including HCV genotype differences, continual exposure to heterologous HCV genotypes and HIV-1 (non-ctade B) co-infection. (2) To determine if immunity is acquired after HCV clearance, whether the immunity is genotype specific and if HlV-1 co-infection alters the immune response. (3) To study the influence of host genetic factors (ie genetic polymorphisms) on HCV clearance and immune response. The results of these studies should provide further insight into the mechanism of HCV clearance and the development of immunity which are critical for the development of effective vaccine and new treatment strategies.